Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke

Abstract

During ischemic stroke, neurons and glia are subjected to damage during the acute and neuroinflammatory phases of injury. Production of reactive oxygen species (ROS) from calcium dysregulation in neural cells and the invasion of activated immune cells are responsible for stroke-induced neurodegeneration. Scientists have failed thus far to identify antioxidant-based drugs that can enhance neural cell survival and improve recovery after stroke. However, several groups have demonstrated success in protecting against stroke by increasing expression of antioxidant enzymes in neural cells. These enzymes, which include but are not limited to enzymes in the glutathione peroxidase, catalase, and superoxide dismutase families, degrade ROS that otherwise damage cellular components such as DNA, proteins, and lipids. Several groups have identified cellular therapies including neural stem cells and human umbilical cord blood cells, which exert neuroprotective and oligoprotective effects through the release of pro-survival factors that activate PI3K/Akt signaling to upregulation of antioxidant enzymes. Other studies demonstrate that treatment with soluble factors released by these cells yield similar changes in enzyme expression after stroke. Treatment with the cytokine leukemia inhibitory factor increases the expression of peroxiredoxin IV and metallothionein III in glia and boosts expression of superoxide dismutase 3 in neurons. Through cell-specific upregulation of these enzymes, LIF and other Akt-inducing factors have the potential to protect multiple cell types against damage from ROS during the early and late phases of ischemic damage.

Laminarin Pretreatment Provides Neuroprotection against Forebrain Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Neuroinflammation in Aged Gerbils

“…During this study, we used pretreatment of gerbils with laminarin and found that SOD1 and SOD2, as endogenous antioxidant enzymes, were markedly increased in CA1 pyramidal neurons before and after IR induction. It has been suggested that increased endogenous antioxidant enzymes prevent the accumulation of ROS [41] and can protect against ischemic injuries [42]. To investigate whether increased SODs protect neurons from IR injury, we examined levels in DHE (a probe to detect superoxide anions) and HNE (a product of lipid peroxidation), as indicators of oxidative stress in the laminarin-IR group and found they were significantly more alleviated in the CA1 pyramidal neurons than those in the vehicle-IR group.…”

Ischaemic and hypoxic conditioning: potential for protection of vital organs

“…Cerebral ischaemia ignites a complex, destructive cascade (Figure ) (Amantea, Greco, Micieli, & Bagetta, ; Davis & Pennypacker, ). Interruption of substrate and O 2 delivery stifles ATP production, causing Gibbs free energy of ATP hydrolysis (Δ G ATP ), the thermodynamic driving force for electrolyte transport and other critical cellular processes, to collapse.…”

“…Cerebral ischaemia ignites a complex, destructive cascade ( Figure 1) (Amantea, Greco, Micieli, & Bagetta, 2018;Davis & Pennypacker, 2017 Damaged neurons release purine nucleotides that provoke microglia to release inflammatory cytokines, drawing macrophages to the lesion (Iadecola & Anrather, 2011). These mechanisms culminate in death of brain parenchyma.…”

Physiological Roles of Metallothioneins in Central Nervous System Diseases

“…While the immunoreactivities of both MT-1/2 and MT-3 stained dominantly in glial cells and were decreased in the spinal cords with ALS patients, 113) another report showed a high expression of MT-3 in ALS. 114) It has been reported that treatment with cytokine leukemia inhibitory factor increases MT-3 expression in glia and boosts expression of superoxide dismutase 3 in neurons. 115) Through such cell-specific upregulation, various factors might have the potential to protect multiple cell types against ROS injury.…”

“…114) It has been reported that treatment with cytokine leukemia inhibitory factor increases MT-3 expression in glia and boosts expression of superoxide dismutase 3 in neurons. 115) Through such cell-specific upregulation, various factors might have the potential to protect multiple cell types against ROS injury. These reports indicate that MTs may have therapeutic potential against motor neuron diseases; however, there is much room for further research.…”